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Critical Issues for Bipolar Disorder Gary S. Sachs, M.D. Harvard Medical School Massachusetts General Hospital October 25, 2005 Psychopharmocological Drugs.

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Presentation on theme: "Critical Issues for Bipolar Disorder Gary S. Sachs, M.D. Harvard Medical School Massachusetts General Hospital October 25, 2005 Psychopharmocological Drugs."— Presentation transcript:

1 Critical Issues for Bipolar Disorder Gary S. Sachs, M.D. Harvard Medical School Massachusetts General Hospital October 25, 2005 Psychopharmocological Drugs Advisory Committee

2 Treatments for Chronic Mental Illness: Principles 1.Approval standards should reflect the interest of patients 2.Research design should be informed by clinical epidemiology 3. The best design methodology is that which optimizes validity and feasibility

3 Bipolar Disorder: Untreated vs Treated Standardized Mortality Ratios Neoplasm Cardio-vascularCerebro-vascular AccidentsSuicideOtherAll Causes Untreated Treated 29.2* * * * * 1.3 * p< p< 0.05 Zurich Cohort, n= Adapted from Angst, 2000

4 Should approval for an acute indication include a requirement for demonstration of long-term efficacy? The Public Health interest is not served by establishing this requirement A policy intended to protect patients against acutely efficacious treatments without proven long-term benefit would benefit few, while depriving many of potentially helpful treatments

5 Is there a need to protect patients from treatments only proven to have short-term efficacy? Patients remain on ineffective medications briefly Effective medications are frequently discontinued over relatively short time periods Most patients using medications long-term are those who responded acutely and either perceive continued benefit or have suffered recurrence when attempting to taper. Based on Altshuler et al. AJP Discontinues after acute response Lack of efficacy Continues long-term treatment Few get long-term treatment in the real world

6 Lithium Use and Discontinuation in a Health Maintenance Organization Length of first continuous period of Lithium use (n=1594) Days Lithium under used - only 8% used Li for 90% of days enrolled - median continuous use = 76 days Adapted from: Johnson, Am J Psychi % 50% 20% 10% 30% 40% 60% 70% 80% 90%

7 Principles of Current Clinical Practice Bipolar disorder is a life long condition in which acute episodes are separated by period of variable remission The episodic nature of bipolar disorder provides the organizing principle of treatment –Episodes are the target of acute and prophylactic treatment –Multiphase Treatment model Acute, Continuation, Maintenance/Discontinuation Maintenance phase treatment reflects prior acute phase experience

8 Multiphase Treatment Strategy Recovering Recovered Natural Course Euthymic Depressed Start Tx Acute Maintenance / Discontinuation Continuation Treated Course

9 Measurement Basic Treatment paradigm is iterative Critical decision point Intervention Menu of reasonable choices Option A Option B Option C $$$$ ££££ EvidenceA-F Individual factors

10 Benefit: Adverse Effect + Cost Each treatment trial is evaluated for Iterative Process: Individual Response Directs Treatment Benefit adverse effects + expense + + ? ? ? ? ? ? ? ? ?

11 Acute episode Recovery Maintenance Therapies in Bipolar Disorder Study Design 4 wks average HRSD <7 & Bech-Rafaelsen <7 Patient and family attend psychoeducational workshop Weekly Acute treatment Recovery ICM + protocol pharmacotherapy IPSRT + protocol pharmacotherapy ICM + protocol pharmacotherapy IPSRT + protocol pharmacotherapy Preventative tx bi-weekly x 12 weeks then monthly x 2 years

12 * p =.03 * Frank et al., Journal of Abnormal Psychology, in press

13 How well do our current treatments work? Acute Bipolar depression –No single agent has FDA approval for treatment of BP depression –STEP-BD and Altshuler/StanleyFBN data indicates need for more efficacious treatments. Acute mania (8 approved agents) –The data from 3-4 week double blind trials indicates that on average participants receiving active treatment finish the study with symptom severity scale scores above the severity score required for study entry. Prophylaxis (4 approved agents) –None consistently efficacious for all relevant outcome variables –None shown effective for subjects remaining well longer than 6 months

14 Acute Bipolar Depression: Placebo controlled therapy Trials with adequate* sample size PositivePositive Li+ Paroxetine Li+ Imipramine *power to detect a difference > 0.8 combination LamotrigineOlanzapineQuetiapine NegativeorFailed Olanzapine + Fluox. monotherapy Imipramine

15 Placebo-Controlled Bipolar Depression Studies with Adequate Samples Tohen et al. Calabrese et al. *p<0.05 vs. PBO OFC-olanzapine fluoxetine combination. Montgomery Asberg Depression Rating Scale. Calabrese et al. J Clin Psychiatry Tohen et al. APA Calabrese et al Calabrese et al APA 2004; * * * * * * * * * * * * * * * * MADRS Change From Baseline

16 16 A rough metric of clinical effectiveness: CE= Response Rate x Completion Rate Study Response rate Completion rate CE NNT OlZ = 39.0% OFC = 56.1% Placebo = 30.4% QTP 300 = 58.2% QTP 600 = 57.6% Placebo = 36.1% Calabrese 1999 Calabrese 2005 Tohen % 64.0% 38.5% 66.9% 54.4% 59.1% 18.9% 35.9% 11.7% 38.9% 31.3% 21.3% % 71.0% LTG 50 = 41% LTG 200 = 51% Placebo = 29% 26.7% 36.2% 20.6%

17 Real World Pharmaco-epidemology New treatment starts at MGH Bipolar Clinic % % % 97 53% 99 54% % Lithium (n=49) Valproate (n=38) Lamotrigine (n=89) Atypical Antipsychotics (n=216) Antidepressants (n=264) Anxiolytics (n=93) Median tx duration (in days) % Recovered/Recovering Majority use < 6 months N =466 with at least 4 visits in year

18 Clinical intent to treat Bipolar Depression Number of Weeks Until Relapse Medication continuation group Medication discontinuation group Altshuler et al. AJP N=1, % remitted Acute Phase Maintenance Phase Results from Stanley Foundation Bipolar Network

19 What is the benefit of standard antidepressants? 84 Remitters = 15% of total Enriched sample of 84 Remitters = 15% of total Adapted from Altshuler et al. AJP ~ 25% relapse < 4 months on or off antidepressant ~ 41% relapse 12 months on antidepressant ~ 71% relapse < 4 months off antidepressant 15% 11% 9% 4% Ever4 months 12 months using Antidepressant % Remaining Well > 1 year Discontinued using Antidepressant <6 months 12m -AD

20 STEP-BD Naturalistic data also indicates great need for better acute treatments Days Well Percent Days well after reaching Recovered Status (8 Wks Well) Majority have remission < 6 months Acute Phase Maintenance Phase 2000 BP Subjects 377 Intent to treat Acute depression Outcome at 90 Days % recovered With AD = 21.5% No Ad = 27.2% Median96.5

21 Psychiatric patients need more acute treatments The proportion of patients achieving an acute benefit is modest There is a compelling need for more acutely efficacious medications Raising the bar to require long-term efficacy is not yet practical Limiting patient choice to only new treatments with proven long-term efficacy will leave potential responders untreated or seeking options unavailable here

22 Less than 10% will benefit The proportion meeting criteria for response or remission in most pivotal trial overstates the benefit of acute treatmentThe proportion meeting criteria for response or remission in most pivotal trial overstates the benefit of acute treatment The proportion depressed meeting DSM-IV criteria for recovered is modest (<20%)The proportion depressed meeting DSM-IV criteria for recovered is modest (<20%) Among those achieving recovery, > 50% experience a recurrence within 3 monthsAmong those achieving recovery, > 50% experience a recurrence within 3 months The vast majority will be negatively impacted by virtue of not having access to acutely beneficial treatmentsThe vast majority will be negatively impacted by virtue of not having access to acutely beneficial treatments

23 Is the Public Health interest well served by requiring demonstration of long term efficacy at time of registration? No compelling benefit –The proportion of patients achieving an acute benefit is modest –There is no surplus of acutely efficacious medications –Patients usually stop ineffective medications quickly –Even effective medications are discontinued over relatively short time periods New obstacles to approval of treatments with acute efficacy will harm patients

24 Critical Design Issues in Conducting Long-Term Trials in Bipolar Disorder Gary S. Sachs, M.D. Harvard Medical School Massachusetts General Hospital October 25, 2005 Psychopharmocological Drugs Advisory Committee

25 Relapse Study Design – Stabilization Period Relapse Study Design – Stabilization Period Design Should Reflect Validity & Feasibility DSM-IV defines recovery from a mood episode as 8 weeks well New proposal calls for 6 months for all chronic conditions EU guidelines are condition dependent: 2 – 6 months Data suggests one duration does not fit all conditions The design should reflect clinical epidemiology of each condition Successful studies use enriched designs Study designed to enrich with atypical patients can be misleading

26 Stabilization Period – EU Guidelines Flexibility Depending on Condition DisorderStabilization Period Major Depressive Disorder8 – 12 weeks Schizophrenia> 6 weeks Manic Episode Bipolar Depression 9 weeks 12 – 26 weeks Generalized Anxiety Disorder8 – 26 weeks Panic Disorder8 – 12 weeks Obsessive Compulsive Disorder> 26 weeks Social Anxiety Disorder8 – 12 weeks

27 STEP – BD Data Time to Relapse and Roughening after Recovery Roughening Full Episode Time to Event/Censoring Survival Distribution Function Steady gradual slope ( 8 weeks stable remission)

28 (Days). Placebo vs Olanzapine in Combination with Lithium or Valproate % Remaining in Remission p=.023 Time to Recurrence Into Mania or Depression OLZ plus Li or VPA, (n=30) Li or VPA, (n=38) Immediate steep slope Randomized after symptomatic remission of mania (YMRS 12) and depression Ham-D 8

29 Tohen et al. Poster presented at XXIII Congress of CINP; 2002; Montreal, Quebec. Time to Recurrence (Days) Lithium or valproate, n=48 Olanzapine plus lithium or valproate, n=46 Time to recurrence of mania after symptomatic remission of mania (YMRS 12) P=0.005 Probability of Remaining in Remission (%) 0% 20% 40% 60% 80% 100% Placebo vs Olanzapine in Combination with Lithium or Valproate Immediate steep slope

30 Week Survival Estimate PBO (n=119) LTG200/400 (n=165) Li (n=120) 2 nd Lamotrigine Maintenance Study* LTG v. PBO, p = Li v. PBO, p = LTG v. Li, p = Randomized subjects well on monotherapy 1 week Immediate steep slope

31 Relapse* Following Open, Prospective Non-Random Antidepressant Discontinuation vs. Continuation 53 BPI 24 BPII Number of Weeks Until Relapse Medication continuation group Medication discontinuation group * Relapse = CGI-S 4 Altshuler et al. AJP Steady gradual slope Enriched Sample of 84 Remitters 6 weeks CGI-S 2

32 Aripiprazole Maintenance of Stability in Bipolar Mania Aripiprazole Placebo Required 6 Weeks Well for Randomization Relative risk = (0.30, 0.913). Data on file, Otsuka America Pharmaceutical, Inc. Days Proportion of Patients Without Relapse Log-rank P value Steady gradual slope

33 Successful studies use enriched designs Total Entering Study Acute Phase Responders = Proportion Randomized Lithium 65% 49% 28% 15% ValproateLTG-POlanzapineAripip MSFBN Primary outcome NS Primary outcome positive Enrichment MostLeast

34 Inherent Maintenance Design Problem Conservative Assumptions – Great Obstacles to FeasibilityConservative Assumptions – Great Obstacles to Feasibility Eligibility Criteria for Randomization = Responder True Responder /All meeting response criteria = 50% Assumes Response for Active = 50% Placebo = 25% Enriched Sample is a composite of 50% True Responders 50% Pseudo Responders In the Double blind Phase: Pseudo Responder Relapse Rates Placebo = Active

35 Inherent Maintenance Design Problem Study Powered for relapse rate Placebo = 60% vs Active 40% Enriched Sample N=200 50% True Responders 50% Pseudo Responders Placebo Cell n=100 50% True Responders 50% Pseudo Responders Active Cell n=100 Subjectsrelapsing 50 Pseudo Responders 50 True Responders Positive result requires active agent sustains effectiveness in at least 80%

36 Inherent Maintenance Design Problem Longer stabilization phase: Study Powered for relapse rate Placebo = 40% vs Active 20% Enriched Sample N=200 50% True Responders 50% Pseudo Responders Placebo Cell n=100 50% True Responders 50% Pseudo Responders Active Cell n=100 Subjectsrelapsing 50 Pseudo Responders 50 True Responders Positive result requires active agent sustains effectiveness in 100%

37 Days Well Percent Days well after reaching Recovered Status (8 Wks Well) produces a sample unrepresentative of patients seeking treatment Use of a 6 month stabilization Majority have remission < 6 months Summary Statistics Number of Obs281 N Missing19 N262 Median96.5 Mean Std Deviation83.21 Mode63 Maximum365 Minimum3.5

38 Narrows the separation Limiting randomization to subjects 6 months will alter study results Antidepressant Discontinuation vs. Continuation Conditional on 6 months well Number of Weeks Until Relapse Medication continuation group Medication discontinuation group

39 Frank et al., Journal of Abnormal Psychology Consequence of 6 Month Stabilization Conditional on remaining well for 6 months Original curves after 6 months

40 Trial Design: Summary of Issues Validity One size does not fit all conditions Data shows what got you well keeps you well 8 wks well is adequate to achieve stabilization 6 month stabilization produces sample unrepresentative of patients seeking treatment 6 month stabilization will make it difficult to detect a true difference between a NME and placebo

41 Trial Design: Summary of Issues Feasibility 6 month stabilization will require a larger sample Larger samples will increase enrollment phase month heightening rater drift and sample variability An increase in enrollment times will delay or prevent patient access to innovative new treatments This proposal is not in the best interest of patients


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